DESCRIPTION (Verbatim from Applicant's Abstract): In the past two decades, there has been a resurgence of serious group A streptococcal (GAS) infections throughout the world. The clinical presentation of these infections has included both aggressive primary disease and the post-infectious syndrome of rheumatic fever. Acute invasive infections are characterized by invasion of the organism from superficial to deep foci, the frequent development of hemodynamic instability (streptococcal toxic-shock), and significant morbidity and mortality, often in previously healthy individuals. No single bacterial determinant appears to be uniquely associated with GAS virulence. Indeed, it is likely that the pathogenesis of GAS infection depends on the carefully regulated expression of a number of virulence factors. Because hyaluronic acid is an important component of human extracellular matrix, and because bacteria must negotiate the extracellular space during invasive infection, one long-standing candidate for a bacterial factor contributing to the pathogenesis of invasive GAS disease is hyaluronate lyase, an enzyme that depolymerizes hyaluronate. Although it was recognized many years ago that GAS can express hyaluronate lyase, the gene encoding the enzyme, the nature of its expression in GAS, and the demonstration of its role in virulence has not been established. Preliminary work in this laboratory has identified the chromosomal gene encoding the GAS hyaluronate lyase. The goals of this proposal are to characterize expression of the hyl gene in GAS strains representing prevalent serotypes recovered from invasive GAS disease and to determine the role of the hyl gene product in GAS virulence using several animal models that in sum capture the diverse clinical manifestations of serious human infection. The identification and characterization of novel GAS virulence determinants is a critical component in the continuing effort to understand and prevent GAS pathogenesis.